Hepatitis B virus (HBV) infection is a major cause of liver-related morbidity and mortality in Europe and worldwide. An estimated 650,000 individuals die each year from liver failure or hepatocellular carcinoma. Even though vaccination programs have led to declines in de novo HBV infections in many countries, chronic hepatitis B (CHB) is a rapidly growing problem in Europe due to immigration of HBV carriers from endemic areas.
From a conceptual standpoint, chronic HBV infection can be classified into three phases (or types of immune responses): immune tolerant, immune active and inactive chronic carrier. These distinct phases of chronic infection correspond with characteristic serologic patterns and correlate with the patient's immune response to HBV. In general, patients with persistent immune active chronic HBV infection receive HBV therapy.
Limited treatment options are available for chronic hepatitis B (CHB). Suppression of viral replication with antivirals such as interferon-alpha and nucleoside/nucleotide analogues (NUCs) is the only way to reduce morbidity and mortality from chronic HBV infection with the ultimate aim of improving survival. Nevertheless, the loss of serum HBsAg and development of anti-HBs antibodies (seroconversion) is the hallmark of a successful immunological response to HBV infection and the closest outcome to clinical cure. Only interferon-alpha has been able to induce significant HBsAg loss but in a relatively low proportion of patients (<10%). Interferons have a high cost, a poor tolerability and some HBV genotypes remain poorly responsive to treatment.
Consequently, NUCs remain the main treatment strategies with five NUCs being approved in Europe to treat CHB. The most potent and preferred drugs, tenofovir and entecavir, have a very favourable side-effect profile and are able to induce HBV DNA suppression in almost all patients. However, life-long therapy is required for the majority of patients under most national and international guidelines. Only very few HBeAg-positive patients, and no HBeAg-negative patients, are able to clear HBsAg even after several years of NUC therapy. The long-term safety of NUC therapy is currently unknown. Therefore, concepts to enable a timely cessation of NUC therapy are urgently needed.
Therapeutic vaccination is a promising intervention for hepatitis B as a way to induce immune control over the disease. T-cell responses have been shown to be critical for clearance of acute HBV infection. However, therapeutic HBV vaccines based on HBsAg have failed to show benefit due to induced immune tolerance from high levels of circulating HBsAg, even under effective antiviral treatment.